Calcium Signaling in the Brain Reward Circuit and Drug Addiction

描述（由申请人提供）：中边缘多巴胺神经元在基于奖励的强化学习中起着核心作用。最近的证据表明，一种病理形式的基于奖励的学习有助于药物成瘾的发展。本研究旨在确定特定钙信号在调节多巴胺神经元的功能输出和可塑性中的作用。我们知道，多巴胺神经元的动作电位放电在出现奖励相关刺激时从强直性单脉冲活动转变为相爆发。这种放电模式转变被认为是由兴奋性谷氨酸能输入触发的，主要是激活NMDA （n -甲基- d -天冬氨酸）型谷氨酸受体。多巴胺神经元爆发导致的阶段性多巴胺释放促进了目标脑区的突触可塑性，从而介导强化学习和药物成瘾的发展。然而，最近的证据表明，多巴胺神经元突触本身的可塑性也可能对这些学习过程至关重要。由突触后动作电位触发的钙信号在大脑突触可塑性中起着至关重要的作用。因此，这一提议的首要假设是，伴随动作电位爆发的大钙瞬态介导了NMDA受体介导的多巴胺神经元传递的长期增强（LTP）的诱导。电生理记录结合细胞内钙的共聚焦成像和笼中化合物的闪光光解作用将在大鼠急性制备的脑切片上进行。第一个目的是确定代谢性神经递质输入和急性精神兴奋剂暴露对突发钙信号的影响。第二个目的是验证NMDA受体介导的LTP可以以依赖于先前代谢性神经递质输入增强的突发诱导钙信号的方式诱导的假设。第三个目的是验证反复暴露在体内的精神兴奋剂会增强突发钙信号和NMDA受体介导的传递的可塑性，从而促进与药物体验相关的环境刺激的学习。从这个项目中获得的结果将提供新的信息，以促进我们对药物成瘾发展背后的神经机制的理解。大脑奖励回路中神经元连接强度的经验依赖性变化被认为是药物成瘾的关键神经机制之一，这可以被视为奖励学习的一种不适应形式。因此，了解导致这些变化的细胞机制将有助于制定药物成瘾的治疗策略。该项目的目标是确定介导这些变化的关键细胞信号及其受成瘾性药物的调节。

DESCRIPTION (provided by applicant): Mesolimbic dopamine neurons play a central role in reward-based reinforcement learning. Recent evidence indicates that a pathological form of reward-based learning contributes to the development of drug addiction. This proposal seeks to define the role of specific calcium signals in regulating the functional output and plasticity of dopamine neurons. It is known that action potential firing of dopamine neurons transitions from tonic single-spike activity to phasic bursts upon presentation of reward-related stimuli. This firing mode transition is thought to be triggered by excitatory glutamatergic inputs predominantly activating NMDA (N-methyl-D-aspartate)-type glutamate receptors. The phasic dopamine release resulting from dopamine neuron bursts acts to promote synaptic plasticity in target brain areas, thereby mediating reinforcement learning and the development of drug addiction. However, recent evidence indicates that plasticity of synapses on dopamine neurons themselves may also be essential for these learning processes. Calcium signals triggered by postsynaptic action potentials are known to play a critical role in the plasticity of synapses in the brain. Therefore, the overarching hypothesis of this proposal is that large calcium transients accompanying bursts of action potentials mediate the induction of long-term potentiation (LTP) of NMDA receptor-mediated transmission onto dopamine neurons. Electrophysiological recording combined with confocal imaging of intracellular calcium and flash photolysis of caged compounds will be performed in acutely prepared brain slices from rats. The first aim is to determine the influence of metabotropic neurotransmitter inputs and acute psychostimulant exposure on burst- induced calcium signals. The second aim is to test the hypothesis that LTP of NMDA receptor- mediated transmission can be induced in a manner dependent on burst-induced calcium signals boosted by preceding metabotropic neurotransmitter inputs. The third aim is to test the hypothesis that repeated psychostimulant exposure in vivo enhances burst-induced calcium signals and the plasticity of NMDA receptor-mediated transmission, which may promote the learning of environmental stimuli associated with drug experience. The results obtained from this project will provide novel information to advance our understanding of the neural mechanisms underlying the development of drug addiction. Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.